The present invention relates to the use of benzydamine and physiologically acceptable acid addition salts thereof in the treatment of pathological conditions caused by TNF (Tumour Necrosis Factor).
Benzydamine (The Merck Index, 9th ed., 1976, page 147 no. 1136) was described for the first time in the patent U.S. Pat. No. 3,318,905 which relates to a group of substances having analgesic, anti-inflammatory and muscle relaxant activity.
Benzydamine has been widely used in practice in human treatment as hydrochloride salt. By the systemic route it is mainly used as an antiphlogistic and analgesic. Topically it is however mainly used for those diseases which involve local inflammation such as for example myalgia, tendinitis, vulvovaginitis, gingivitis, stomatitis, mucositis of the oral cavity and so forth.
Moreover benzydamine salicylate has been used in rheumatic disorders.
TNF is a non-glycosylated polypeptide having relative molecular mass (M.sub.r) of 17,500 (17.5 KDa) and known amino acid sequence, and it is supposed that the active form is trimeric (Old L. J. "Science", 1985, 230, 630-632; Beutler B. et al. "Nature", 1986, 320, 585-588; Jones E. Y. et al. "Nature", 1989, 338, 225-228; Corti A. et al. "Biochem. J., 1992, 284, 905-910).
TNF, also known as alpha TNF or cachectin belongs to the family of cytokines and as such plays a part in the stimulation of immune responses to defend the organism from external attacks (Epstein F. H. "The New England J. of Med.", 1987, 316, 379-385; Urdal D. L. "Annual Reports in Med. Chem.", 1991, 26, 221-227).
On the other hand, an excessive action by TNF may in itself become an actual pathogenetic cause given the considerable toxicity of TNF (Waage A. et al. "Immunological Reviews", 1992, No. 127, 221-230).
It is thus acknowledged that TNF plays a very important role in some very serious pathological conditions of an acute and chronic nature such as, for example, septic shock and cachexia (Epstein F. H., loc. cit.; Waage A. et al., loc. cit.) and multiple sclerosis (Dijkstra D. C. et al., Trends in Pharm. Sc., 14, 124-129, 1993).
Therefore, while for many years researches about TNF have aimed at studying its properties, structure and preparation, in recent years the need has been felt for agents capable of interfering with the production or action of TNF, to be used as therapeutical means in pathologies wherein toxic, bacterial, viral or endogenous agents lead, by stimulating the macrophages, to the production of toxic concentrations of TNF.
Thus compounds capable of interfering with TNF, albeit by different mechanisms, have been identified.
More particularly, it has been reported that some compounds are capable of protecting some particularly sensitive cell lines from the toxic action of TNF.
Suramin (EP-A-0 486 809), thalidomide (Sampaio E. P. "J. Exp.
Med.", 173, 699-703, 1991) and some derivatives of glutarimides such as cyclohexymide ("Transplant Proc." 23, 254-5, 1991) interfere, albeit in different ways and with different specificity, in the production of TNF.
In contrast, vinigrol (PCT-WO-91/07953; Weber E. "J. Org. Chem." 52, 5292-5293, 1987) interferes with the action of TNF without altering its synthesis.
Before an antagonistic action in respect of TNF had been identified, there was no connection between these compounds either as far as regards their structure or clinical use.
In fact suramin, i.e. 8,8'-(carbonylbis(imino-3,1-phenylene carbonylimino (4-methyl-3,1-phenylene) carbonylimino)) bis-1,3,5-naphthalene trisulfonic acid, was known as trypanocide. Cyclohexymide, i.e. 4-(2-(3,5-dimethyl-2-oxo-cyclohexyl)-2-hydroxyethyl)-2,6-piperidindione was known as fungicide. Vinigrol, i.e. 4,8a(1H)-diol,4,4a,5,6,7,8-hexahydro-3-(hydroxymethyl)-8,9-dimethyl-12-(1- methylethyl)-(1R-1alpha, 4beta, 4alpha beta, 5alpha, 8beta, 8alpha beta, 9S*, 12S*))-1,5-butanonaphthalene was known as an hypotensive and an anti-platelet aggregant.
Finally, experiments performed by the Applicant have shown that conventional anti-inflammatory agents such as ibuprofen and indomethacin do not antagonise TNF (see Example 1).